Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF3 subfamily, TRAF domain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF3 was first described as a molecule that binds the cytoplasmic tail of CD40. However, it is not required for CD40 signaling. More recently, TRAF3 has been identified as a key regulator of type I interferon (IFN) production and the mammalian innate antiviral immunity. It mediates IFN responses in Toll-like receptor (TLR)-dependent as well as TLR-independent viral recognition pathways. It is also a key element in immunological homeostasis through its regulation of the anti-inflammatory cytokine interleukin-10. TRAF3 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 331 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 410
Cdd:cd03777     1 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 411 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 490
Cdd:cd03777    81 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 160

                         170       180
                  ....*....|....*....|....*.
gi 1867163858 491 VAQTVLENGTYIKDDTIFIKVIVDTS 516
Cdd:cd03777   161 VAQTVLENGTYIKDDTIFIKVIVDTS 186

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1867163858 136 HLKNdCHFEELPCVRPDCKEKVLRKDLRDHVEKACKYREATCSH----CKSQVPMIALQKH 192
Cdd:pfam02176   1 HLET-CPFFPIPCPNGCCKKKILREDLPDHLELDCPKAEVPCPFkvfgCKEDVKREALQRH 60

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF3 subfamily, TRAF domain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF3 was first described as a molecule that binds the cytoplasmic tail of CD40. However, it is not required for CD40 signaling. More recently, TRAF3 has been identified as a key regulator of type I interferon (IFN) production and the mammalian innate antiviral immunity. It mediates IFN responses in Toll-like receptor (TLR)-dependent as well as TLR-independent viral recognition pathways. It is also a key element in immunological homeostasis through its regulation of the anti-inflammatory cytokine interleukin-10. TRAF3 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 331 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 410
Cdd:cd03777     1 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 411 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 490
Cdd:cd03777    81 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 160

                         170       180
                  ....*....|....*....|....*.
gi 1867163858 491 VAQTVLENGTYIKDDTIFIKVIVDTS 516
Cdd:cd03777   161 VAQTVLENGTYIKDDTIFIKVIVDTS 186

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1867163858 136 HLKNdCHFEELPCVRPDCKEKVLRKDLRDHVEKACKYREATCSH----CKSQVPMIALQKH 192
Cdd:pfam02176   1 HLET-CPFFPIPCPNGCCKKKILREDLPDHLELDCPKAEVPCPFkvfgCKEDVKREALQRH 60

TRAF-type zinc finger;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1867163858 197 CPCVVVSCPHKCSVQTLLRSELSAHLSE-CVNAPSTCSFKRYGC--VFQGTNQQ 247
Cdd:pfam02176   5 CPFFPIPCPNGCCKKKILREDLPDHLELdCPKAEVPCPFKVFGCkeDVKREALQ 58

Uncharacterized conserved protein, contains RING Zn-finger [General function prediction only];

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1867163858  52 KCEKCHLVLCSPKQTE-CGHRFCESCMAALLSSSSPKCTACQ-ESIVKDKVFKDNCCKREI 110
Cdd:COG5222   276 KCPLCHCLLRNPMKTPcCGHTFCDECIGTALLDSDFKCPNCSrKDVLLDGLTPDIDKKLEV 336

Zinc finger, C3HC4 type (RING finger); The C3HC4 type zinc-finger (RING finger) is a cysteine-rich domain of 40 to 60 residues that coordinates two zinc ions, and has the consensus sequence: C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C where X is any amino acid. Many proteins containing a RING finger play a key role in the ubiquitination pathway.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1867163858  56 CHLVLCSPKQ----TECGHRFCESCMAALLSSSSPKCTAC 91
Cdd:pfam00097   1 CPICLEEPKDpvtlLPCGHLFCSKCIRSWLESGNVTCPLC 40

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF3 subfamily, TRAF domain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF3 was first described as a molecule that binds the cytoplasmic tail of CD40. However, it is not required for CD40 signaling. More recently, TRAF3 has been identified as a key regulator of type I interferon (IFN) production and the mammalian innate antiviral immunity. It mediates IFN responses in Toll-like receptor (TLR)-dependent as well as TLR-independent viral recognition pathways. It is also a key element in immunological homeostasis through its regulation of the anti-inflammatory cytokine interleukin-10. TRAF3 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 331 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 410
Cdd:cd03777     1 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 411 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 490
Cdd:cd03777    81 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 160

                         170       180
                  ....*....|....*....|....*.
gi 1867163858 491 VAQTVLENGTYIKDDTIFIKVIVDTS 516
Cdd:cd03777   161 VAQTVLENGTYIKDDTIFIKVIVDTS 186

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF5 subfamily, TRAF domain, C-terminal MATH subdomain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF5 was identified as an activator of nuclear factor-kappaB and a regulator of lymphotoxin-beta receptor and CD40 signaling. Its interaction with CD40 is indirect, involving hetero-oligomerization with TRAF3. In addition, TRAF5 has been shown to associate with other TNFRs including CD27, CD30, OX40 and GITR (glucocorticoid-induced TNFR). It plays a role in modulating Th2 immune responses (driven by OX40 costimulation) and T-cell activation (triggered by GITR). It is also involved in osteoclastogenesis. TRAF5 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 369 GVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCARVYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVT 448
Cdd:cd03780     1 GKLIWKVTDYKMKKKEAVDGHTVSIFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVT 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1867163858 449 LMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVFVAQTVLENG--TYIKDDTIFIKVIVD 514
Cdd:cd03780    81 LMLLDQSGKKNHIMETFKADPNSSSFKRPDGEMNIASGCPRFVAHSVLENAknTYIKDDTLFLKVAVD 148

Tumor Necrosis Factor Receptor (TNFR) Associated Factor (TRAF) family, TRAF1 subfamily, TRAF domain, C-terminal MATH subdomain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF1 expression is the most restricted among the TRAFs. It is found exclusively in activated lymphocytes, dendritic cells and certain epithelia. TRAF1 associates, directly or indirectly through heterodimerization with TRAF2, with the TNFR family receptors TNFR-2, CD30, RANK, CD40 and LMP1, among others. It also binds the intracellular proteins TRADD, TANK, TRIP, RIP1, RIP2 and FLIP. TRAF1 is unique among the TRAFs in that it lacks a RING domain, which is critical for the activation of nuclear factor-kappaB and Jun NH2-terminal kinase. Studies on TRAF1-deficient mice suggest that TRAF1 has a negative regulatory role in TNFR-mediated signaling events. TRAF1 contains one zinc finger and one TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 369 GVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCARVYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVT 448
Cdd:cd03779     1 GTFLWKITDVSQKQRESSHGRDVSLCSPAFYTAKYGYKVCLRLYLNGDGAGKGTHISLFFVIMKGEYDALLPWPFRHKVT 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1867163858 449 LMLMDQgSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVFVAQTVLEN--GTYIKDDTIFIKVIVD 514
Cdd:cd03779    81 FMLLDQ-NNREHVIDAFRPDLSSASFQRPVSDMNVASGCPLFFPLKKLQSpkHAYCKDDTIYIKCVVD 147

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF6 subfamily, TRAF domain, C-terminal MATH subdomain; composed of proteins with similarity to human TRAF6, including the Drosophila protein DTRAF2. TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF6 is the most divergent in its TRAF domain among the mammalian TRAFs. In addition to mediating TNFR family signaling, it is also an essential signaling molecule of the interleukin-1/Toll-like receptor superfamily. Whereas other TRAF molecules display similar and overlapping TNFR-binding specificities, TRAF6 binds completely different sites on receptors such as CD40 and RANK. TRAF6 serves as a molecular bridge between innate and adaptive immunity and plays a central role in osteoimmunology. DTRAF2, as an activator of nuclear factor-kappaB, plays a pivotal role in Drosophila development and innate immunity. TRAF6 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 369 GVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCARVYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVT 448
Cdd:cd03776     1 GIYVWKIKNFSNLRRSMEAGSPVVIHSPGFYTSPPGYKLCARLNLSLPEARCPNYISLFVHLMQGENDSHLDWPFQGTIT 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1867163858 449 LMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIAS-GCPVFVAQTVLENGTYIKDDTIFIKVIV 513
Cdd:cd03776    81 LTLLDQSEPRQNIHETMMSKPELLAFQRPTTDRNPKGfGYVEFAHIEDLLQRGFVKNDTLLIKIEV 146

MATH (meprin and TRAF-C homology) domain; an independent folding unit with an eight-stranded beta-sandwich structure found in meprins, TRAFs and other proteins. Meprins comprise a class of extracellular metalloproteases which are anchored to the membrane and are capable of cleaving growth factors, extracellular matrix proteins, and biologically active peptides. TRAF molecules serve as adapter proteins that link cell surface receptors of the Tumor Necrosis Factor and 1nterleukin-1/Toll-like families to downstream kinase cascades, which results in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses in the immune and inflammatory systems. Other members include the ubiquitin ligases, TRIM37 and SPOP, and the ubiquitin-specific proteases, HAUSP and Ubp21p. A large number of uncharacterized members mostly from lineage-specific expansions in C. elegans and rice contain MATH and BTB domains, similar to SPOP. The MATH domain has been shown to bind peptide/protein substrates in TRAFs and HAUSP. It is possible that the MATH domain in other members of this superfamily also interacts with various protein substrates. The TRAF domain may also be involved in the trimerization of TRAFs. Based on homology, it is postulated that the MATH domain in meprins may be involved in its tetramer assembly and that the MATH domain, in general, may take part in diverse modular arrangements defined by adjacent multimerization domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 369 GVLIWKIRDYKRRKQEavmgktlSLYSQPFYTGyfGYKMCARVYLNGDGmGKGTHLSLFFVIMRGEYDaLLPWPFKQKVT 448
Cdd:cd00121     1 GKHTWKIVNFSELEGE-------SIYSPPFEVG--GYKWRIRIYPNGDG-ESGDYLSLYLELDKGESD-LEKWSVRAEFT 69

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1867163858 449 LMLMDQgSSRRHLGDAFKPDPNSssfkkptgEMNIASGCPVFVAQTVLENGTYIKDDTIFIKVIVD 514
Cdd:cd00121    70 LKLVNQ-NGGKSLSKSFTHVFFS--------EKGSGWGFPKFISWDDLEDSYYLVDDSLTIEVEVK 126

Modified RING finger, HC subclass (C3HC3D-type), found in tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) and similar proteins; TRAF5, also known as RING finger protein 84 (RNF84), is an important signal transducer for a wide range of TNF receptor superfamily members, including tumor necrosis factor receptor 1 (TNFR1), TNFR2, CD40, and other lymphocyte costimulatory receptors, RANK/TRANCE-R, ectodysplasin-A Receptor (EDAR), lymphotoxin-beta receptor (LT-betaR), latent membrane protein 1 (LMP1), and IRE1. It functions as an activator of NF-kappaB, MAPK, and JNK, and is involved in both RANKL- and TNFalpha-induced osteoclastogenesis. It mediates CD40 signaling by associating with the cytoplasmic tail of CD40. It also negatively regulates Toll-like receptor (TLR) signaling and functions as a negative regulator of the interleukin 6 (IL-6) receptor signaling pathway that limits the differentiation of inflammatory CD4(+) T cells. TRAF5 contains an N-terminal domain with a modified C3HC3D-type RING-HC finger and several zinc fingers, and a C-terminal TRAF domain that comprises a coiled coil domain and a conserved TRAF-C domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1867163858  48 EDKYKCEKCHLVLCSPKQTECGHRFCESCMAALLS-SSSPKCTACQESIVKDKVF 101
Cdd:cd16642     2 EDRYKCATCHFVLHNPHQTGCGHRFCQHCILSLLElNTTPICPIDKETIKSDEVF 56

Modified RING finger, HC subclass (C3HC3D-type), found in tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and similar proteins; TRAF6, also known as interleukin-1 signal transducer or RING finger protein 85 (RNF85), is a cytoplasmic adapter protein that mediates signals induced by the tumor necrosis factor receptor (TNFR) superfamily and Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) family. It functions as a mediator involved in the activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and interferon regulatory factor pathways, as well as in IL-1R-mediated activation of NF-kappaB. TRAF6 is also an oncogene that plays a vital role in K-RAS-mediated oncogenesis. TRAF6 contains an N-terminal domain with a modified C3HC3D-type RING-HC finger and several zinc fingers, and a C-terminal TRAF domain that comprises a coiled coil domain and a conserved TRAF-C domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1867163858  50 KYKCEKCHLVLCSPKQTECGHRFCESCMAALLSSSSPKCTACQESIVKDKVFKDNCCK 107
Cdd:cd16643     1 KYECPICLMALREPVQTPCGHRFCKACILKSIREAGHKCPVDNEPLLENQLFPDNFAK 58

RING finger, HC subclass, found in tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and similar proteins; TRAF2, also known as tumor necrosis factor type 2 receptor-associated protein 3, is an E3 ubiquitin-protein ligase that was identified as a 75 kDa tumor necrosis factor receptor (TNF-R2)-associated signaling protein. It interacts with members of the TNF receptor superfamily and connects the receptors to downstream signaling proteins. It also mediates K63-linked polyubiquitination of RIP1, a kinase pivotal in TNFalpha-induced NF-kappaB activation. Moreover, TRAF2 regulates peripheral CD8(+) T-cell and NKT-cell homeostasis by modulating sensitivity to IL-15. It also acts as an important biological suppressor of necroptosis. It inhibits TNF-related apoptosis inducing ligand (TRAIL)- and CD95L-induced apoptosis and necroptosis. TRAF2 contains an N-terminal domain with a typical C3HC4-type RING-HC finger and several zinc fingers, and a C-terminal TRAF domain that comprises a coiled coil domain and a conserved TRAF-C domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 1867163858  50 KYKCEKCHLVLCSPKQTECGHRFCESCMAALLSSSSPKCTAC 91
Cdd:cd16639     1 KYLCSDCRNILRRPFQAQCGHRYCSYCLKKILSSGPQKCAAC 42

Meprin family, Beta subunit, MATH domain; Meprins are multidomain extracellular metalloproteases capable of cleaving growth factors, cytokines, extracellular matrix proteins, and biologically active peptides. They are composed of two related subunits, alpha and beta, which form homo- or hetro-complexes where the basic unit is a disulfide-linked dimer. The beta subunit is a type I membrane protein, which forms homodimers or heterotetramers (alpha2beta2 or alpha3beta). Meprin beta shows preference for acidic residues at the P1 and P1' sites of its substrate. Among its best substrates are growth factors and chemokines such as gastrin and osteopontin. Both alpha and beta subunits contain a catalytic astacin (M12 family) protease domain followed by the adhesion or interaction domains MAM, MATH and AM. The MATH and MAM domains provide symmetrical intersubunit disulfide bonds necessary for the dimerization of meprin subunits. The MATH domain may also be required for folding of an activable zymogen.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 372 IWKIRDYKRrkqeaVMGKTL---SLYSQPFYTGYfGYKMCARVYLNGDGMGKGtHLSLFFVIMRGEYDALLPWPFK-QKV 447
Cdd:cd03782     5 IWHIRNFTQ-----LLATTPpngKIYSPPFLSST-GYSFQVGLYLNGTDDYPG-NLAIYLHLTSGPNDDQLQWPCPwQQA 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 448 TLMLMDQGSS-RRHLG-------DAFK--------------------PDPNSSSFKKPTGemniaSGCPVFVAQTVLENG 499
Cdd:cd03782    78 TMMLLDQHPDiRQRMSnqrsvttDPNMtstdsdeyfwddprkvgsevTDTDGSTFYRGPG-----YGTSAFITHLRLRSR 152

                         170
                  ....*....|
gi 1867163858 500 TYIKDDTIFI 509
Cdd:cd03782   153 DFIKGDDVIF 162

Modified RING finger, HC subclass (C3HC3D-type), found in uncharacterized proteins similar to tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4); This subfamily corresponds to a group of uncharacterized proteins that shows high sequence similarity with tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4). TRAF4, also known as cysteine-rich domain associated with RING and Traf domains protein 1, or metastatic lymph node gene 62 protein (MLN 62), or RING finger protein 83 (RNF83), is a member of TRAF protein family, which mainly function in the immune system, where they mediate signaling through tumor necrosis factor receptors (TNFRs) and interleukin-1/Toll-like receptors (IL-1/TLRs). It also plays a critical role in the nervous system, as well as in carcinogenesis. Like TRAF4, members of this subfamily contain a modified C3HC3D-type RING-HC finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1867163858  47 VEDKYKCEKCHLVLCSPKQ-TECGHRFCESCMAALLsSSSPKCTACQESIVKD 98
Cdd:cd23126     1 LDKKYECPVCCQVLRYPVQfEECGHRVCSSCLPELL-RVEPRCPIDQGPIDRD 52

DNA repair protein rad18; All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858  44 VKTVEDKYKCEKCHLVLCSPKQTECGHRFCESCMAALLsSSSPKCTAC----QESIVkdkvfKDNCCKREILalqiycrn 119
Cdd:TIGR00599  20 LYPLDTSLRCHICKDFFDVPVLTSCSHTFCSLCIRRCL-SNQPKCPLCraedQESKL-----RSNWLVSEIV-------- 85

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 120 ESRGCAEQLMLGHLLVHLKNDCHFEELPCVRPDCKEKVLRKDLRDHVEKACK--YREATCSHCKSQVPMIALQKHEDTDC 197
Cdd:TIGR00599  86 ESFKNLRPSLLEFLRIPKTTPVENPDLAGPENSSKIELIEESESDGVDAEDEdlQRSATSSRALAARSTADILQLSSDPS 165

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1867163858 198 PCV------------VVSCPhKCSVQTLLRSELSAHLSECVNAPSTCSFKRYGCVFQGTNQ 246
Cdd:TIGR00599 166 KRNdadyrseppnegLVQCP-ICQQRMPEKAVERHLDSECLGSPSLGASTTFPTESNPHNK 225

RING finger, HC subclass, found in radiation sensitivity protein 5 (RAD5) and similar proteins; RAD5, also known as revertibility protein 2 (REV2), or DNA repair protein RAD5, is a probable helicase, and a member of the UBC2/RAD6 epistasis group. It functions with the DNA repair protein RAD18 in error-free postreplication DNA repair. It is involved in the maintenance of wild-type rates of instability of simple repetitive sequences such as poly(GT) repeats. It may also be involved in maintaining a balance which acts in favor of error-prone non-homologous joining during DNA double-strand breaks repairs. It recruits the UBC13-MMS2 dimer to chromatin for DNA repair. RAD5 contains a typical C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 1867163858  66 TECGHRFCESCMAALL-----SSSSPKCTACQESIVKDKVFK 102
Cdd:cd23131    22 TECGHSFCEDCLLEYIefqnkKKLDLKCPNCREPISKYRLLK 63

Meprin family, Alpha subunit, MATH domain; Meprins are multidomain extracellular metalloproteases capable of cleaving growth factors, cytokines, extracellular matrix proteins, and biologically active peptides. They are composed of two related subunits, alpha and beta, which form homo- or hetro-complexes where the basic unit is a disulfide-linked dimer. The alpha subunit is synthesized as a membrane spanning protein, however, it is cleaved during biosynthesis and loses its transmembrane domain. It oligomerizes into large complexes, containing 10-100 subunits (dimers that associate noncovalently), which are secreted as latent proteases and can move through extracellular spaces in a nondestructive manner. This allows delivery of the concentrated protease to sites containing activating enzymes, such as sites of inflammation, infection or cancerous growth. Meprin alpha shows preference for small or hydrophobic residues at the P1 and P1' sites of its substrate. Both alpha and beta subunits contain a catalytic astacin (M12 family) protease domain followed by the adhesion or interaction domains MAM, MATH and AM. The MATH and MAM domains provide symmetrical intersubunit disulfide bonds necessary for the dimerization of meprin subunits. The MATH domain may also be required for folding of an activable zymogen.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 372 IWKIRDYKRRKQEAVmgKTLSLYSQPFYTGYfGYKMCARVY-LNGDGMGKGTHLSLFFVIMRGEYDALLPWP-FKQKVTL 449
Cdd:cd03783     5 VWRVRNFSQILENTT--KGDVLQSPRFYSPE-GYGYGVSLYpLSNESDYSGNYTGLYFHLCSGENDAVLEWPaLNRQAII 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163858 450 MLMDQ--------GSSRRHLGDAFKPDP---NSSSFKKPT--GEMNIASGC--------PVFVAQTVLENGTYIKDDTIF 508
Cdd:cd03783    82 TVLDQdpdvrlrmSSSRSFTTDKSQTSSainGTLRWDRPSrvGTYDTSCDCfrgidfgwSTFISHSQLRRRSFLKNDDLI 161

                  ...
gi 1867163858 509 IKV 511
Cdd:cd03783   162 IFV 164

Variant RING finger, HC subclass (C4C4-type), found in retinoblastoma-binding protein 6 (RBBP6) and similar proteins; RBBP6, also known as proliferation potential-related protein, protein P2P-R, retinoblastoma-binding Q protein 1 (RBQ-1), or p53-associated cellular protein of testis (PACT), is a nuclear E3 ubiquitin-protein ligase involved in multiple processes, such as the control of gene expression, mitosis, cell differentiation, and cell apoptosis. It plays a role in both promoting and inhibiting apoptosis in many human cancers, including esophageal, lung, hepatocellular, and colon cancers, familial myeloproliferative neoplasms, as well as in human immunodeficiency virus-associated nephropathy (HIVAN). It functions as an Rb- and p53-binding protein that plays an important role in chaperone-mediated ubiquitination and possibly in protein quality control. It acts as a scaffold protein to promote the assembly of the p53/TP53-MDM2 complex, resulting in an increase of MDM2-mediated ubiquitination and degradation of p53/TP53, and leading to both apoptosis and cell growth. It is also a double-stranded RNA-binding protein that plays a role in mRNA processing by regulating the human polyadenylation machinery and modulating expression of mRNAs with AU-rich 3' untranslated regions (UTRs). Moreover, RBBP6 ubiquitinates and destabilizes the transcriptional repressor ZBTB38 that negatively regulates transcription and levels of the MCM10 replication factor on chromatin. Furthermore, RBBP6 is involved in tunicamycin-induced apoptosis by mediating protein kinase (PKR) activation. RBBP6 contains an N-terminal ubiquitin-like domain and a C4C4-type RING finger, whose overall folding is similar to that of the typical C3HC4-type RING-HC finger. RBBP6 interacts with chaperones Hsp70 and Hsp40 through its N-terminal ubiquitin-like domain. It promotes the ubiquitination of p53 by Hdm2 in an E4-like manner through its RING finger. It also interacts directly with the pro-proliferative transcription factor Y-box-binding protein-1 (YB-1) via its RING finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1867163858  49 DKYKCEKCHLVLCSPKQTEC-GHRFCESCMAALLSSSSPKCTACQESIVKDKV 100
Cdd:cd16620     2 DELKCPICKDLMKDAVLTPCcGNSFCDECIRTALLEEDFTCPTCKEPDVSPDA 54

Modified RING finger, HC subclass (C3HC3D-type), found in tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) and similar proteins; TRAF4, also known as cysteine-rich domain associated with RING and Traf domains protein 1, metastatic lymph node gene 62 protein (MLN 62), or RING finger protein 83 (RNF83), is a member of the TRAF protein family, which mainly function in the immune system, where they mediate signaling through tumor necrosis factor receptors (TNFRs) and interleukin-1/Toll-like receptors (IL-1/TLRs). It also plays a critical role in nervous system, as well as in carcinogenesis. TRAF4 promotes the growth and invasion of colon cancer through the Wnt/beta-catenin pathway. It contributes to the TNFalpha-induced activation of the 70 kDa ribosomal protein S6 kinase (p70s6k) signaling pathway, and activation of transforming growth factor beta (TGF-beta)-induced SMAD-dependent signaling and non-SMAD signaling in breast cancer. It also enhances osteosarcoma cell proliferation and invasion by the Akt signaling pathway. Moreover, TRAF4 is a novel phosphoinositide-binding protein modulating tight junctions and favoring cell migration. TRAF4 contains an N-terminal domain with a modified C3HC3D-type RING-HC finger and several zinc fingers, and a C-terminal TRAF domain that comprises a coiled coil domain and a conserved TRAF-C domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1867163858  50 KYKCEKCHLVLCSPKQ-TECGHRFCESCMAALLSSSSPKC 88
Cdd:cd16641     1 RLLCPLCRLPMREPVQiSTCGHRFCDTCLQEFLSEGVFKC 40

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1867163858   53 CEKCH-LVLCSPKQTECGHRFCESCMAALLSSSSPKC 88
Cdd:smart00184   1 CPICLeEYLKDPVILPCGHTFCRSCIRKWLESGNNTC 37

RING finger, HC subclass, found in breast cancer type 1 susceptibility protein (BRCA1) and similar proteins; BRCA1, also known as RING finger protein 53 (RNF53), is a RING finger protein encoded by the tumor suppressor gene BRCA1 that regulates all DNA double-strand break (DSB) repair pathways. BRCA1 is frequently mutated in patients with hereditary breast and ovarian cancer (HBOC). Its mutation is also associated with an increased risk of pancreatic, stomach, laryngeal, fallopian tube, and prostate cancer. It plays an important role in the DNA damage response signaling and has been implicated in various cellular processes such as cell cycle regulation, transcriptional regulation, chromatin remodeling, DNA DSBs, and apoptosis. BRCA1 contains an N-terminal C3HC4-type RING-HC finger, and two BRCT (BRCA1 C-terminus domain) repeats at the C-terminus.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1867163858  53 CEKCHLVLCSPKQTECGHRFCESCMAALLSSSSPK--CTACQESIVK 97
Cdd:cd16498    19 CPICLELLKEPVSTKCDHQFCRFCILKLLQKKKKPapCPLCKKSVTK 65

RING finger, HC subclass, found in RING finger protein 114 (RNF114) and similar proteins; RNF114, also known as zinc finger protein 228 (ZNF228) or zinc finger protein 313 (ZNF313), is a p21(WAF1)-targeting ubiquitin E3 ligase that interacts with X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) and may play a role in p53-mediated cell-fate decisions. It is involved in the immune response to double-stranded RNA in disease pathogenesis. Moreover, RNF114 interacts with A20 and modulates its ubiquitylation. It negatively regulates nuclear factor-kappaB (NF-kappaB)-dependent transcription and positively regulates T-cell activation. RNF114 may play a putative role in the regulation of immune responses, since it corresponds to a novel psoriasis susceptibility gene, ZNF313. RNF114, together with three closely related proteins: RNF125, RNF138 and RNF166, forms a novel family of ubiquitin ligases with a C3HC4-type RING-HC finger, a C2HC-, and two C2H2-type zinc fingers, as well as a ubiquitin interacting motif (UIM).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1867163858  50 KYKCEKCHLVLCSPKQTECGHRFCESCMAALLSSSSPKCTACQ 92
Cdd:cd16540     1 RFTCPVCLEIFETPVRVPCGHVFCNACLQECLKPKKPVCAVCR 43

RING finger, HC subclass, found in ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1); UHRF1, also known as inverted CCAAT box-binding protein of 90 kDa, nuclear protein 95, nuclear zinc finger protein Np95 (Np95), RING finger protein 106, transcription factor ICBP90, or E3 ubiquitin-protein ligase UHRF1, is a unique chromatin effector protein that integrates the recognition of both histone PTMs and DNA methylation. It is essential for cell proliferation and plays a critical role in the development and progression of many human carcinomas, such as laryngeal squamous cell carcinoma (LSCC), gastric cancer (GC), esophageal squamous cell carcinoma (ESCC), colorectal cancer, prostate cancer, and breast cancer. UHRF1 can acts as a transcriptional repressor through its binding to histone H3 when it is unmodified at Arg2. Its overexpression in human lung fibroblasts results in downregulation of expression of the tumor suppressor pRB. It also plays a role in transcriptional repression of the cell cycle regulator p21. Moreover, UHRF1-dependent repression of factors can facilitate the G1-S transition. It interacts with Tat-interacting protein of 60 kDa (TIP60) and induces degradation-independent ubiquitination of TIP60. It is also a N-methylpurine DNA glycosylase (MPG)-interacting protein that binds MPG in a p53 status-independent manner in the DNA base excision repair (BER) pathway. In addition, UHRF1 functions as an epigenetic regulator that is important for multiple aspects of epigenetic regulation, including maintenance of DNA methylation patterns and recognition of various histone modifications. UHRF1 contains an N-terminal ubiquitin-like domain (UBL), a tandem Tudor domain (TTD), a plant homeodomain (PHD) domain, a SET and RING finger associated (SRA) domain, and a C-terminal C3HC4-type RING-HC finger. It specifically binds to hemimethylated DNA, double-stranded CpG dinucleotides, and recruits the maintenance methyltransferase DNMT1 to its hemimethylated DNA substrate through its SRA domain. UHRF1-dependent H3K23 ubiquitylation has an essential role in maintenance DNA methylation and replication. The tandem Tudor domain directs UHRF1 binding to the heterochromatin mark histone H3K9me3 and the PHD domain targets UHRF1 to unmodified histone H3 in euchromatic regions. The RING-HC finger exhibits both autocatalytic E3 ubiquitin (Ub) ligase activity and activity against histone H3 and DNMT1.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1867163858  42 KFVKTVEDKYKCEKCHLVLCSPKQTECGHRFCESCMAALLSSSSPKCTACQESIVKDKVFKDN 104
Cdd:cd16769     4 LFLSKVEETFQCICCQELVFRPITTVCQHNVCKDCLDRSFRAQVFSCPACRYDLGRSYAMQVN 66